2023年 新着論文 18 細胞情報学分野から論文が発表されました

HNRNPU facilitates antibody class-switch recombination through C-NHEJ promotion and R-loop suppression

Cell Rep. 2023 Mar 20;42(3):112284. doi: 10.1016/j.celrep.2023.112284. Online ahead of print.

Authors

Ahmed M Refaat  1 Mikiyo Nakata  2 Afzal Husain  3 Hidetaka Kosako  4 Tasuku Honjo  5 Nasim A Begum  2

Affiliations

  • 1 Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan; Zoology Department, Faculty of Science, Minia University, El-Minia 61519, Egypt.
  • 2 Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
  • 3 Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, Uttar Pradesh 202002, India.
  • 4 Division of Cell Signaling, Institute of Advanced Medical Sciences, University of Tokushima, Tokushima 770-8503, Japan.
  • 5 Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan. Electronic address: honjo@mfour.med.kyoto-u.ac.jp.

Free article

Abstract

B cells generate functionally different classes of antibodies through class-switch recombination (CSR), which requires classical non-homologous end joining (C-NHEJ) to join the DNA breaks at the donor and acceptor switch (S) regions. We show that the RNA-binding protein HNRNPU promotes C-NHEJ-mediated S-S joining through the 53BP1-shieldin DNA-repair complex. Notably, HNRNPU binds to the S region RNA/DNA G-quadruplexes, contributing to regulating R-loop and single-stranded DNA (ssDNA) accumulation. HNRNPU is an intrinsically disordered protein that interacts with both C-NHEJ and R-loop complexes in an RNA-dependent manner. Strikingly, recruitment of HNRNPU and the C-NHEJ factors is highly sensitive to liquid-liquid phase separation inhibitors, suggestive of DNA-repair condensate formation. We propose that HNRNPU facilitates CSR by forming and stabilizing the C-NHEJ ribonucleoprotein complex and preventing excessive R-loop accumulation, which otherwise would cause persistent DNA breaks and aberrant DNA repair, leading to genomic instability.

Keywords: C-NHEJ; CP: Immunology; CP: Molecular biology; CSR; G-quadruplex; HNRNPU; R-loop; shieldin.

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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